Comparison of the degradation of type II collagen and proteoglycan in nasal and articular cartilages induced by interleukin-1 and the selective inhibition of type II collagen cleavage by collagenase

Objective. To compare interleukin-1 alpha (IL-1 alpha)induced degradation o f nasal and articular cartilages in terms of proteoglycan loss and type II collagen cleavage, denaturation, and release; to examine the temporal relat ionship of these changes; and to investigate the effects of an inhibitor of collagenase 2 and collagenase 3 on these catabolic processes. Methods, Discs of mature bovine nasal and articular cartilages were culture d with or without human IL-1 alpha, (5 ng/ml) with or without RS102,481, a selective synthetic inhibitor of collagenase 2 and collagenase 3 (matrix me talloproteinase 8 [MMP-8] and MMP-13, respectively) but not of collagenase 1 (MMP-1), Immunoassays were used to measure collagenase-generated type II collagen cleavage neoepitope (antibody COL2-3/4C(short)) and denaturation ( antibody COL2-3/4m), as well as total type Il collagen content (antibody CO L2-3/4m) in articular cartilage and culture media. A colorimetric assay was used to measure total proteoglycan concentration (principally of aggrecan) as sulfated glycosaminoglycans (sGAG). Results. IL-1 alpha initially Induced a decrease in tissue proteoglycan con tent in nasal cartilage, A progressive loss of proteoglycan was noted durin g culture in articular cartilages, irrespective of the presence of IL-1 alp ha, In both cartilages, proteoglycan loss was followed by IL-1 alpha-induce d cleavage of type II collagen by collagenase, which was often reflected by increased denaturation, The inhibitor BS102,481 had no clear effect: on th e reduction in proteoglycan content (measured by sGAG) and collagen denatur ation in either cartilage, but at 10 nM it inhibited the enhanced cleavage of type II collagen, partially in nasal cartilage and completely in articul ar cartilage. Conclusion, IL-1 alpha-induccd cleavage and denaturation of type II collage n is observed in bath hyaline cartilages and is secondary to proteoglycan l oss, It probably involves different collagenases, since there is no evidenc e of a rate-limiting role for collagenase 1 in articular cartilage, unlike the ease for nasal cartilage, Inhibitors of this kind may be of value in th e treatment of cartilage damage in arthritis, Also, the ability to detect t he release of type II collagen collagenase-generated fragments from degrade d cartilage offers the potential to monitor cartilage collagen damage and i ts control in vivo.